Ying Sun, M.D., Ph.D.

Funded in December, 2006: $600000 for 3 years

Unraveling the Mystery of the Immunologic Cascade that Occurs in Allergic Asthma

Consortium researchers will explore the possibility that allergic asthma results from release by immune white blood cells of an inflammatory substance that directs immune T cells to attack lung tissue.

Asthma is characterized by infiltration and accumulation in inflamed lungs of a specific type of memory T cells (specific types of CD4+T cells) and “eosinophils,” which are immune white blood cells that produce inflammation. In people with asthma, these immune T cells are thought to become overly sensitive to otherwise harmless agents, remember the allergen, and react whenever the allergen is encountered. The T cells maintain chronic allergic inflammation and generate rapid inflammation whenever asthma sufferers are exposed to allergens. Scientists have little understanding, however, of the nature of these memory T cells in humans and how they are regulated and maintained.

The King's College and M.D. Anderson Center researchers recently discovered that a substance (called TSLP), found in cells in the lining of the lung, activates immune dendritic cells (DCs) during allergic inflammation. The DCs stimulate the memory T cells to respond to the allergen and to proliferate. TSLP, they suggest, may constitute the missing link in this immunological cascade that stimulates and maintains memory T activation in asthma. Additionally, the M.D. Anderson researchers found that eosinophils appear to produce the inflammation-producing substance, an immune “cytokine” called IL-25. This raises the possibility that eosinophil production of IL-25 may exert a critical role in maintaining the allergen-specific memory T cells in allergic inflammation, providing a feedback loop for further activation of these memory T cells. This suggestion turns current thinking upside down. Instead of eosinophils being the consequence of the memory T cell actions, the eosinophils would actually be driving the memory T cells through production of IL-25. The researchers will combine their expertise in immunology (M.D. Anderson) and molecular immunopathology (Kings College) to test this hypothesis in laboratory studies of tissue obtained from people with asthma.

Significance: If the research demonstrates that interaction between immune eosinophils and memory T cells occurs in asthma via eosinophil production of the inflammatory cytokine IL-25, the findings may lead to novel means to block this inflammatory cytokine or its effect on immune T cells.

Inflammation with eosinophils and Th2 T cells is a major pathological feature of the target organ mucosa in asthma and atopic dermatitis. While Th2 T cells are well known to regulate eosinophil function through Th2 cytokines such as IL-5, relatively little attention has been paid to the reverse process, that is, the possibility that eosinophil products can regulate Th2 cell function. Strong expression of local tissue lymphopoietins such as TSLP at epithelial surfaces can activate dendritic cells to induce a Th2 permissive microenvironment and expression of new genes on committed CRTh2+CD4+ memory T cells. One such gene is the receptor for the cytokine IL-25, one of IL-17 family of cytokines. Systemic over-expression of IL-25 in animal results in Th2-skewed immune responses and pathological changes in the respiratory and gut mucosa reminiscent of allergic inflammation.

Our preliminary data suggest that this cytokine may play an important role in the mechanistic “cross talk” between Th2 T cells and eosinophils. We have found that eosinophils are the major source of IL-25. Conversely, IL-25R expression is confined principally to memory Th2 T cells. These observations suggest the hypotheses that (1) IL-25 plays an amplifying role in allergic inflammation; (2) CRTh2+CD4+ T cells are an important target for IL-25 in allergic inflammation; (3) eosinophils are a significant source of IL-25. To explore these hypotheses, we will use the well characterized late-phase cutaneous reaction to allergen challenge in the skin of atopic subjects. In this model, skin biopsies can be obtained from individual subjects at intervals of up to 72 hours following cutaneous allergen challenge, so that the time courses of cellular infiltration and cytokine expression can be charted. In this project we will track infiltration of CRTh2+CD4+ T memory cells, as well as IL-25 and IL-25 receptor immunoreactive cells. We will also identify the phenotypes of the latter cells. This will be accomplished using techniques including double, sequential immunohistochemistry (IHC) and IHC/in situ hybridization. We will also examine bronchial mucosal biopsies from asthmatics and controls in a similar fashion. We see these ex vivo, dynamic experiments as complementing and amplifying static experiments addressing the functional effects of IL-25 on CRTh2+CD4+ T cells and the production of IL-25 by eosinophils. We can also make comparisons with disease severity and examine expression of IL-25 in relation to other asthma-relevant cytokines.

The data obtained from these experiments will allow us to establish new roles for CRTh2+CD4+ T cells and eosinophils in allergic inflammation and will open new avenues for therapeutic intervention.

Ying Sun, M.D., Ph.D.

Ying Sun, M.D., Ph.D., is a Senior Lecturer in the Division of Asthma, Allergy & Lung Biology, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, U.K. His laboratory focuses on roles of inflammatory cells and mediators involved in pathogenesis of asthma and atopic allergic diseases, including cytokines, chemokines, leukotrienes, and their receptors.Yong-Jun Liu, M.D., Ph. D., is the Professor and Vivian L. Smith Distinguished Chair in Immunology, and Director for the Center for Cancer Immunology Research, at the University of Texas M.D. Anderson Cancer Center in Houston. Dr. Liu received his M.D. from Norman Bethune University in China and Ph.D. (Immunology) from the Birmingham University School of Medicine, United Kingdom, where he completed a research fellowship. Subsequently, Dr. Liu served as Charge de Researche and later Matre de Researche in the Laboratory for Immunological Research at Schering-Plough, Dardilly, France. He later served as Senior Staff Scientist at the DNAX Research Institute prior to accepting his appointment to the University of Texas faculty. His honors include selection in 2004 as a George and Barbara Bush Fellow for Innovative Cancer Research. His research interests focus on dendritic cell (DC) development, the function of dendritic cell subsets in innate and adaptive immunity, T cell activation and differentiation, and cytokines an immuno-therapy for cancers. Specific programs in his lab deal with biology of human plasmacytoid dendritic cells(pDC), also known as type 1 IFN-producing cells (IPCs); the function of pDCs in human diseases; and human thymic stromal lymphopoietin (TSLP) function in DC-mediated peripheral T cell responses, in particular allergic responses and selection of regulatory T cells in the thymus.

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